Naphthyl acetaldehyde derivatives;methods of use thereof;and processes for the preparation thereof

ABSTRACT

2-(2&#39;&#39;-Naphthyl) acetaldehyde derivatives optionally substituted at the 2 position and/or positions C-1&#39;&#39;,4&#39;&#39;,5&#39;&#39;,7&#39;&#39; or 8&#39;&#39;; and/or position C-6&#39;&#39; or positions C-5&#39;&#39; and 7&#39;&#39; exhibit anti-inflammatory, analgesic, antipyretic and anti-pruritic activity.

United States Patent 1 [111 3,821,253

Fried et al. June 28, 1974 l l NAPHTHYL ACETALDEHYDE [51] Int. Cl C07d 13/04 DERIVATIVES; METHODS OF USE [58] Field of Search 260/3409. 512 C THEREOF; AND PROCESSES FOR THE PREPARATION THEREOF [56] References Cited [75} Inventors: John H. Fried; [en T. llarrison, UNITED STATES PATENTS both 2.542.937 2/l95l Miescher et al. 260/599 Assignee; Synex corporaflon Apanado 3,644,429 Hajos Cl 3] X Panama Primary Examiner-Donald G. Daus [22] Filed 1972 Ass/slam Examiner-James H. Tumipseed {21] Appl. No.: 222,278 Attorney, Agent, or Firm -William B. Walker; Gerald Rcmed USo. Application Dam A. Blaufarb; Joseph l. Hirsch [60] Division of Scr. No. 8 l4,855. April 9. I969, which is a continuation-in-part of Scr. No. 741900, July 2, ABSTRACT 1968' PM 2(2-Naphthyl) acetaldehy le derivatives optionally Us. Cl IIIIIII H 260/3409 260/3401 260/3459 substituted at the 2 position and/0r positions C- 260/470, 260/473 F. 260/475 FR, 260/488 CD, 260/5l5 A, 260/5l5 R. 260/516 260/5l8 A. 260/5l8 R, 260/5I9, 260/520. 260/566 A, 260/566 AC l',4,5',7' or 8; and/or position C-6' or positions C-5' and 7 exhibit anti-inflammatory, analgesic. antipyretic and anti-pruritic activity.

16 Claims, No Drawings NAIHTIIYL ACETALDEHYDE DERIVATIVES; METHODS OF USE THEREOF; AND PROCESSES FOR THE PREPARATION THEREOF More particularly. the present novel invention is directed to 2-(2'-naphthyl) acetaldehydes derivatives which exhibit anti-inflammatory. analgesic. antipyretic. and anti-pruritie activity.

The 2-(2'-naphthyl) acetaldehydes derivatives are illustrated by the following formulas (the arabic numbers in formulas l and ll designate the position of the 2-( 2'-naphthyl)acetaldehyde nomenclature used herein )2 it R R1 RI nl r it n R. m Rll rt rt Rio rv n

wherein. R is -CHRR. CH(OH)(NH,) or --(C- H(OH)(SO Y); wherein R and R are nlkoxy. cycloalkoxy. cycloalkylmethoxy. 2-cycloalkylethoxy. 3- cyeloalkylpropoxy. monocyelie arylmethoxy. 2- phenylethoxy. J-phenylpropoxy. alkanoyloxy. eycloalkanoyloxy. cyeloalkyl acetoxy. cycloalkylpropionyloxy. monocyclic arylaeetoxy'. or R and R taken together are =0. NR. 3-hydroxypropylene-l .2-dioxy. OCHR--CHRO- or OCHR.CRR--CH- R..O-; wherein R is alkyl. cycloalkyl. cycloalkylmethyl, 2-cycloalkyl ethyl. monoeyclic arylmethyl. phenethyl. hydroxy. alkoxy. cycloalkoxy. cycloalkyl methoxy. Z-cycloalkyiethoxy. benzyloxy. 2- phenylethoxy. amino or carbamoylamino; each of R and R. independently of each other is hydrogen. alkyl. cycloalkyl. cycloalkylmethyl. Z-cycloalkylethyl. monoeyclic arylmethyl. or monocyclie aryl; R is hydrogen, methyl; ethyl or propyl; Y is sodium or potassium. one of R and R is hydrogen. the other is hydrogen. methyl. ethyl or difluoromethyl; or R and R taken together are methylene. halomethylene or ethylene;

R (at position C-l.4 or 8) is hydrogen. alkyl. trifluoromethyl. fluoro. chloro. hydroxy. a conventional hydrolyzable ester. oxyether or thioether;

R (at position C-5. 6 or 7) is alkyl. cycloalkyl. hydroxymethyl. alkoxymethyl. trifluoromethyl. vinyl. ethynyl. fluoro. chloro. hydroxy. a conventional hydrolyzable ester. oxyether. thioether. formyl. acetyl or monocyclic aryl'.

each of R'. R" (at position C-l. 4. 7 or 8). R" and R. is alkyl. fluoro. chloro. hydroxy. a conventional hydrolyzable ester. oxyether or thioether. provided that when one of R and R" or one of R and R is hydroxy. oxyether or thioether. the other is the identical group or alkyl. fluoro. chloro. or a conventional hydrolyzable ester; and R (at position C-S) is alkyl. fluoro. chloro. bromo. hydroxy. a conventional hydrolyzable ester. oxyether or thioether; provided when one of R and R" (at position C5) is hydroxy. oxyether or thioether. the other is the identical group of alkyl. fluoro. chloro. bromo (R only i. e.. only R" is bromo. R is not bromo) or a conventional hydrolyzable ester.

In the preferred embodiment of the present invention. R and R are methoxy. ethoxy. propoxy. cyclopentyloxy. cyclohexyloxy. benzyloxy. phenethyloxy. tolyloxy. acetoxy. propionyloxy. valeryloxy. caproyloxy. cyclopentylcarbonyloxy. cyclohexylcarbonyloxy. phenylacetoxy or tolylacetoxy; or R and R taken together are =0. methylimino. ethylimino. isopropylimino. cyclopentylimino. cyclohexylimino. benzylimino. p-methylbenzylimino. phenethylimino. phenylimino. tolylimino. hydroxyimino. methoxyimino. ethoxyimino. i-propoxyimino. cyclopentyloxyimino. cyclohexyloxyimino. benzyloxyimino. pmethylbenzyloxyimino. phenethyloxyimino. aminoimino. carbamoylamino. ethylenedioxy. 1.2- propylenedioxy. l.3propanedioxy. 3-hydroxypropylenel .2-dioxy. 2.3-butanedioxy. l .2- diphenylethylenedioxy. l.2dicyclopentylethylenedioxy. l.2-dibenzylethylenedioxy. 2.2-dimethyl-l.3- propanedioxy or Z-phenyl-l.3-propanedioxy; Y is sodium; one of R and R is hydrogen. the other is hydrogen. methyl or difluoromethyl; or R and R taken together are methylene or difluoromethylene; R (at position Cl. 4 or 8) is hydrogen. methyl. ethyl. isopropyl. trifluoromethyl. fluoro. chloro. methoxy. methoxymethyloxy. difluoromethoxy. methylthio. methoxymethylthio or difluoromethylthio; R (at position C-5. 6 or 7) is methyl. ethyl. isopropyl. cyclopropyl. trifluoromethyl. vinyl. ethynyl. fluoro. chloro. methoxy. methoxymethyloxy. difluoromethoxy. methylthio. methoxymethylthio or difluoromethylthio. each of R. R (at position C-l. 4. 7 or 8). R and R is methyl. ethyl. isopropyl. fluoro. chloro. methoxy. methoxymethyloxy. dilluoromethoxy. methylthio. methoxymethylthio. or difluoromethylthio. provided that when one of R or R". or one of R" and R" is methoxy. methoxymethyloxy. difluoromethoxy. methylthio. methoxymethylthio or difluoromethylthio. the other is the identical group of methyl. ethyl. isopropyl. fluoro or chloro; and R (at position G5) is methyl. ethyl. isopropyl. fluoro. chloro. methoxy. methoxymethyloxy. difluoromethoxy. methylthio. methoxymethylthio or dilluoromethylthio; provided when one of R and R (at position G5) is methoxy. methoxymethyloxy. difluoromethoxy. methylthio. methoxymethylthio. or difluoromethylthio. the other is the identical group or methyl. ethyl. isopropyl. fluoro. chloro or bromo (R" only). R (at position O5) is methyl. ethyl. isopropyl. fluoro. chloro. bromo. trifluoromethyl. methoxy. methoxymethyloxy. difluoromethoxy. methylthio. methoxymethylthio or difluoromethylthio. the other is the identical group or methyl. ethyl. isopropyl. fluoro. chloro or chloro (R only).

By the term "alkyl" is meant branched or straight chain hydrocarbon atoms. such as methyl. ethyl. propyl. isopropyl. butyl. tertiarybutyl. pentyl. hexyl. and. the like. By the term cyeloalkyl is meant cyclic hydrocarbon groups of three to seven carbon atoms. such as cyciopropyl, eyclopentyl. cyciohexyl. and the like.

The term monocyclic aryl" defines a phenyl group optionally substituted with one to two methyl. ethyl. isopropyl. methoxy. hydroxy. fiuoro. or chloro groups. Typical monocyclic aryls include phenyl. 2-tolyl, 3- tolyl. 4-toiyl. 2.4-dimethylphenyl. 2.6-dimethylphenyl. B-ethylphenyl. 4-ethylphenyl. 4-isopropylphenyl. 2- methoxy. 4-methoxyphenyl. 2.4-dimethoxyphenyl. 3- hydroxyphenyl. 2.6-dihydroxyphenyl. 2-chlorophenyl. 2.6-dichlorophenyl. 3-lluorophenyl. 4-fluorophenyl. 2.4-difluorophenyl. 2.3-difluorophenyl. 2.3.4- trifluorophenyl. paracltlorophenyl. 2.4- dihydroxyphcnyl. 2.4-dirhethoxyphenyl and the like.

The term "alkanoyloxf' defines a straight or branched saturated hydrocarbon carbonyloxy group of from one to l2 carbon atoms. Typical alkanoyloxy groups include acctoxy. propionyloxy. butyryloxy. 4- methylvalryloxy. caproyloxy. Z-methylbutyryloxy. capryloxylosy. pelargyloxy. capryloxy. 9- mcthylcapryloxy. lauroyloxy. and the like.

The term alkoxy defined a straight or branched chain hydrocarbon ether group of six or less carbon atoms, including mcthoxy. ethoxy. 2-propoxy. propoxy. butoxy. B-pentoxy. and the like. By the term "alkoxymethyloxy is meant methylether groups substituted with one alkoxy group; typical alkoxymethyloxy groups include methoxymethyloxy. ethoxymethyloxy. isopropoxymethyloxy. and the like.

By the term "alkylthio" is meant straight or branched chain hydrocarbon thioether groups of six or less carbon atoms. including methylthio. ethylthio. propylthio. Z-propylthio. 2-butylthio. pentylthio. S-hexylthio. and the like. By the term alkoxymethylthio" is meant methylthio other groups substituted with one alkoxy group. such as methoxymethylthio. cthoxymcthylthio. 2-propoxymethylthio. and the like.

The term "cycloalkyloxy defines a cyclic hydrocarbon ether group of from three to sever carbon atoms. Typical cycloalkyloxy include cyclopentyloxy and cyclohcxyloxy.

The term monocyclie aralkyloxy is meant an alkoxy substituent substituted with one monocyclic aryl group. Typical monocyclic aralkyloxy include: 2.6- dimethylbenzyloxy and p-chlorophenylthyloxy.

The term "alkanoyloxy" defines an alkylcarbonyloxy group. Typical alkanoyloxy groups include acetoxy. butyryloxy. and capryloxy. The term "cycloalkanoyloxy defines a monocyclic cycloaikylcarbonyloxy group. The term "monocyelic aralkanoyloxy defines an aralkyl carbonyloxy group such as phenylacetyloxy.

By the term halomethylene is meant nonoor dihalo-mcthylenc groups wherein halo is fluoro or chloro. The preferred halomethylenes include fluoromethylene. difiuoromethylene. fluorochloromethylene and chloromethylene.

The term "conventional hydroiyzable ester". as used herein. denotes those hydrolyzable ester groups conventionally employed in the art. preferably those derived from hydrocarbon carboxylic acids or their salts. The term "hydrocarbon carboxylic acid" defines both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation (including aromatic). can be ofstraight chain, branched chain. or cyclic structure and preferably contain from one to twelve carbon atoms. Typical conventional hydrolyzable esters thus included within the scope of the term and the instant invention are acetate. propionate. 2- methyl propionate. butyrate. valerate. caproate. enanthate. caprylate. benzoate. phenylacetate, diethylacetate. trimethylacetate. t-butylacetate. cyclohexylacetate. cyclopentylpropionate. adamantoate. bicyclo[2.2.2]octyl carboxylate. hemisuceinate. hemiadipate. hemi-B.B-dimethylglutarate and the like.

The term "oxyether". as used herein. denoted those ether groups conventionally employed in the art. preferably those derived from straight chain. branched chain. aromatic hydrocarbons and 0x0 heterocyclic hydrocarbons. The term hydrocarbon" defines both sat urated and unsaturated hydrocarbons. These designated hydrocarbons are optionally substituted with groups such as hydroxy. alkoxy. halo. alkylthio. and the like. Preferably the hydrocarbons contain from one to twelve carbon atoms. Typical oxyethers thus include alkoxy. difluoromethoxy. alkoxymethyloxy. tetrahydrofuran-2'-yloxy. tetrahydropyran-2'-yloxy and 4'- alkoxytetrahydropyran-4'-yloxy.

The term thioethcr. as used herein. denotes those thio ether groups conventionally employed in the art. preferably those derived from straight chain. branched chain. cyclic and aromatic hydrocarbons. The term "hydrocarbon" defines both saturated and unsaturated hydrocarbons. These hydrocarbons are optionally substituted with groups such as hydroxy. alkoxy. alkylthio. halo and the like. Preferably the hydrocarbons contain from one to twelve carbon atoms. Typical thioethers thus include alkylthio. difiuoromethylthio. alkoxymethylthio. and the like.

When one of Rand R is hydrogen and the other is methyl. ethyl or difluorom e thyl. the compounds of formulas i. ii. iii and IV exist as pairs of enantiomorphs. Each enantiomorph or optical isomer of the compounds of formulas i. ii. iii and W is included within the present invention. in some instances. one enantiomorph exhibits greater anti-inflammatory. analgesic. anti-pyretic and/or anti-pruritic activity than the corresponding other enantiomorph. Nevertheless. the present compounds of formulas i. ll and Ill and IV that exist as pairs of enantiomorphs can be administered as mixtures of enantiomorphs or as individual resolved enantiomorphs.

Preferably the individual resolved enantiomorphs or optical isomers of the compounds of formulas i. ll. ill and IV are prepared from the corresponding individual resolved enantiomorphs or optical isomers of the starting material. Alternatively. the optical isomers can be resolved by conventional means. such as selective biological degradation. The resolved enantiomorph of formulas i. ll. ill and W and the corresponding resolved starting material will not necessarily have the same optical rotation although they will have the same absolute configuration.

The 2-(2'-naphthyl) acetaldehydes and derivatives thereof of formulas i. ll. Ill and IV exhibit antiinflammatory. analgesic. anti-pyretic and anti-pruritic activity. Accordingly. these compounds are employed in the present method of effecting treatment of inflammation. pain. pyrexia and pruritus in mammals. such as mice. rats. dogs. monkeys or humans.

These compounds are useful in the treatment of inflammation of the skin, respiratory tract. muscularskeletal systems. joints. internal organs. and tissues.

Accordingly. these compounds are useful in the treatment of conditions characterized by inflammation, such as contact dermatitis. allergic conditions. burns. rheumatism. contusion. arthritus. bone fracture. posttraumatic conditions and gout. in those cases in which the above conditions include pain. pyrexia and pruritus. coupled with the inflamation. the instant compounds are useful for relief of these conditions as well as the inflammation. The instant compounds are useful in the treatment of pain associated with post-operative conditions. post-traumatic conditions. post-partum conditions. dysmenorrhea. burns. gout. contusions. neuralgia. neuritis, headache and rheumatic fever. As stated above. these compounds also exhibit anti-pyretic activity; accordingly. these compounds are useful in the treatment of pyrexia where reduction of a fever is indicated. for example. in the treatment ofhigh fevers associated with diseases such as rheumatic fever. bronchitis. pneumonia. typhoid fever. and Hodgkins disease. The present compounds are also useful in the 1: tme t of pruritus where the condition exists contemporaneously with inflammation. pain and/or fever. Moreover. the compounds are useful for treating pruritus per Although the above compounds of formulas l-IV exhibit anti-inflammatory. analgesic. anti-pyretic and atrti-pruritic activity. certain groups of the above compounds exhibit remarkably enhanced specific activity while retaining the other types of activity. For example. the compounds of formula ll where R is at position 06 exhibit enhanced anti-inflammatory activity together with analgesic. anti-pyrctic and anti-pruritic activity. Accordingly. the compounds of formula II would be very useful in treating a condition characterized by a high degree of inflammation together with moderate degree of pain. The and 7 substituted compounds of formula II and the compounds of formula IV exhibit superior analgesic activity together with antiinflammatory. anti-pyretic and anti-pruritic activity. Accordingly. the 5 and 7 substituted compounds of formulti I and the compounds of formula IV are very useful to treat conditions characterized by a high degree of pain together with a moderate degree of inflammation, fever and pruritus.

The preferred manner of rral administration provides the use of a convenient daily dosage regimen which can be adjusted according to the degree of aflliction. Generally. a daily dose of from 0.01 mg. to 100 mg. of the active compound per kilogram of body weight of the mammal is employed. Most conditions respond to treatment comprising a dosage level in the order of 1 mg. to 5 mg. per kilogram of body weight per day. For such oral administration. a pharmaccutically acceptable non-toxic composition formed by the incorporation of any of the normally employed excipicnts. Suitable pharmaceutical cxcipicnts include starch. glucose. lactose. sucrose. gelatin. malt. rice. flour. chalk. silica gel. magnesium carbonate. magnesium stearatc. sodium stcaratc. glyceryl monostcratc. talc. sodium chloride. dried skim milk. glycerol. propylene glycol. water. ethanol. and the like. These compositions take the form of solutions suspensions. tablets. pills. capsules. powders sustained release formulations. and the like. in addition. these compounds can be administered in conjunction with other medicinal agents depending upon the specific condition being treated.

A measure of anti-infalmmatory activity according to the carrageenin induced edema assay of Winter et al.. Proceedings ofthe Society for Experimental Biology and Medicine III. 544 (1962) shows the following: that 2-(6'-methoxy-2'-naphthyl) propionaldehyde to have over three times the activity of phenylbutazone; that the semicarbazone of 2-(6'-methoxy-2-naphthyl) propionaldehyde has over three times the activity of phenyl butazoncd; that l-hydroxyimino-2-to" methoxy-2'-naphthyl) propane has over two times the activity of phenylbutazone'. that l.l-dimethyl-2-(6- methoxy-2'-naphthyl) propane is as active as phenylbutazone; and that the sodium bisulfite addition product of 2-(6'-methoxy-2'-naphthyl) propionaldehyde has about three times the activity of phenylbatazone.

Similar standard assays'to measure anti-pyretic activities show 2-(6'-methoxy-2'-naphthyl) propionaldehyde and the sodium bisulfite addition product thereof to have over l4 and 17 times. respectively. the anti-pyretic activity of aspirin.

included within the compounds of formulas I. ii. iii and IV are the novel 2-(2'-naphthyl) acetaldehyde derivatives of the following formulas:

RH R7 R. R, R.

V VI

It" II R n VIII VII wherein.

R. R and R are as defined above. R" (at position C-l. 4 or 8) is trifluoromcthyl. fluoro. chloro. hydrloxy. a conventional hydrolyzable ester or thioct er;

R (at position C-S or 7) is alkyl. cycloalkyl. hy-

droxymethyl. alkoxymethyl. trifluoromethyl. vinyl. cthynyl. fluoro. chloro. hydroxy. a conventional hydrolyzlablc ester. oxyether. thiocther. formyl. acetyl or arcy R" is alkyl. cycloalkyl, hydroxymcthyl. alkoxymethyl. trifluoromethyl. vinyl. cthynyl. fluoro. chloro. hydroxy. a conventional hydrolyzablc ester. alkoxymethyloxy. difluoromethoxy. tctrahydropyran-2-yloxy. tetrahydrofuran-2-yloxy. 4'-alkoxy-tetrahydropyran- 4'-yloxy; thioethcr. formyl. acetyl or aryl'. and

each of R" and R" (at positions C-t. 4. 7 or 8). R" and R" is alkyl. fluoro. chloro. hydroxy. a conventional hydrolyzablc ester. oxycther or thioether; provided that when one of R" or R. or one of R or R is hydroxy.

oxyether or thioether the other is the identical group or all-tyl. iluoro. or chloro or a conventional hydrolyzble ester; and

R" (at position C-) is alkyi. fluoro. chloro. bromo. hydroxy. a conventional hydrolyzable ester. oxyether or thiocther; provided when one of R and R" (at position (-5) is hydroxy. oxyethcr or thiocther the other is the identical group or nlkyl. fluoro. ehloro. hromo (R" only). or a conventional hydroly'zaltle ester.

in the preferred embodiment of the novel compounds of formulas V. Vl. Vll. Vlll and 1X. R and R are methoxy. ethyoxy cyclopentyloxy. cyclohexyloxy. benzyloxy. phenethyloxy. tolyloxy. acetoxy. propionyloxy. valeryloxy. eaproyloxy. cyclopentylcarbonyloxy. cyclohexylcarbonyloxy. phenylacetyloxy or tolylacetoyloxy; or R and R taken together are =0. methylimino. ethylimino. isopropylimino. cyclopentylimino. cyclohexylimino. benzylimino. pmethylbenzylimino. phenethvlimino. phenylimino. tolylimino. hydroxyimino. metnoxyimino. ethoxyimino. isopropoxyim no. cyclopentyloxyimino. cyclohexyloxyimino. benzyloxyimino. p-methylbenzyloxyimino. phenethyloxyimino. aminoimino. carbamoylamino. ethylenedioxy. Llpropylenedioxy. l.3-propanedioxy. 3-hydroxypropylene-l.Z-dioxy. 2.3-butanedioxy. 1.2- diphenylcthylencdioxy. l.2-dicyclopentylethylenedioxy. l.2-dibenzylcthylencdioxy. 2.2-dimethyl-l.3- propanedioxy or 2-phcnyl-l.3-propanedioxy; Y is sodium; one of R and R is hydrogen. the other is hydrogen. methyl or difluoromethyl; or R and R taken togcther are methylene or difluoromethylcnc; R (at position C-l. 4 and 8) is trifluoromethyl. fluoro. chloro. methylthio. methoxymethylthio or difluoromethylthio'. R" (at position C-S or 7) is methyl. ethyl. isopropyl. cyclopropyl. trifluoromethyl. vinyl. ethynyl. fiuoro. chloro. methoxy. methoxymcthyloxy. difluoromethoxy. methylthio. methoxymethylthio or difluoromethylthio. R" is methyl. ethyl. isopropyl. cyclopropyl. trifiuoromethyl. vinyl. ethynyl. fiuoro. chloro. methoxymethyloxy. fdilluoromcthoxy. methylthio. methoxymethylthio or difiuoromethylthio; each of R". R (at position C-l. 4. 7 or 8). R" and R is methyl. ethyl. isopropyl. fiuoro. chloro. methoxy. methoxymcthyloxy. difluoromcthoxy. methylthio. methoxymethylthio or difluoromcthylthio'. provided that when one of R' or R". or one of R'" or R is methoxy. methoxymethyloxy. difiuoromethoxy. methylthio. methoxymcthylthio. or difluoromethylthio. the other is the identical group or methyl. ethyl. isopropyl fluoro or chloro; and R' (at position O5) is methyl. ethyl. isopropyl. fluoro. chloro. bromo. methoxy. methoxymethyloxy. difiuoromethoxy. methylthio. methosymethylthio o r difluoromethylthio; provided that when one of R" or R. position C-S) is methoxy. methoxymethyloxy. difluoromethoxy. methylthio. mcthoxymethylthio or difluoromethylthio. the other is the identical group or methyl. ethyl. isopropyl. fiuoro. chloro or bromo (R" only i.e.. only R" is bromo. R" is not bromo).

An especially preferred group of novel 2-(2'- naphthyl) acetaldchyde derivatives are those of formulas VI. VII. Vlll and 1X wherein R. R. R. R. R. R. R". R". R". R' and R are defined in the above immediate paragraph.

The present compounds of formulas i. ii. iii and W (wherein R is CHO) are prepared from the corresponding Z-naphthyl acetic acid derivatives or esters thereof via a novel process which can be illustrated by the following reaction scheme A:

SCHEMEA n a a a c o o R i on o x xi wherein.

R and R are as defined above and R" is hydrogen or alkyl. in the above scheme. the naphthyl moiety of the 2-(2'-naphthyl) acetic acid derivatives of formula X and of the 2-(2'-naphthyl) acetaldehyde derivatives of formula Xl are substituted with l a R group at position Cl. 4. or 8; (2) at R group at position C-S. 6 or 7; (3) a R' at position C-6 and a R at position C- l. 4.5. 7 or 8'. or (4) a R and R group at positions C-5 and CJ respectively.

The novel process of Scheme A is conducted by treating the starting compound of formula X. a 2-(2'- naphthyl) acetic acid derivative or ester thereof. with lithium aluminum hydride in an inert organic ether solvent. such as diethyl ether. tetrahydrofuran. and the like. If a free 2-(2'-naphthyl) acetic acid derivative is used as a starting material. at least 0.75 molar equivalents of lithium aluminum hydride are used. and preferably about I.() to 2.5 molar equivalents are used. If an ester of a 2-(2'-naphthyl) acetic acid derivative is used as a starting material. at least 0.5 molar equivalents of lithium aluminum hydride are used. and preferably about 0.6 to 2.0 molar equivalents are used. The reduction is carried out at a temperature between 0C and the boiling point of the solvent employed. preferably between 15C and 35C. The second step of the above process consists of adding ethyl acetate to the reaction mixture diluting the resulting mixture with water (at least 8 ml. of water per gram of alkali metal hydride). filtering and evaporating it.'The resulting residue is treated with chromium trioxide in acetic acid or pyridine or acetone containing 8N sulfuric acid. The pro cess is carried out at a temperature between 0C and C. preferably the reaction temperature is between 5C and 30C. At least two-thirds molar equivalents of chromium trioxide are used per molar equivalent of the acid starting material and preferably about L5 to about 2.5 molar equivalents of chromium trioxide are used.

Alternatively. the first step can be carried out by treating the compound of fomtula X with diborane in tetrahydrofuran at about room temperature. One to 2 equivalents of diborane per molar equivalent of the starting compound are usually sufficient.

Alternatively. the second step can be carried out by treating the residue obtained from the first step of the reaction with dicyclohexylcarbodiimide (DCC) and anhydrous phosphoric acid in dimethyl sulfoxide at about room temperature. Generally. 3 molar equivalents of DCC and one-half molar equivalents of anhydrous phosphoric acid are used per molar equivalent of the starting compound of formula X used in the first step.

At the completion of the above process. the compound of formula Xl. the product. is isolated by con- *octancdiol.

ventional means. For example. the reaction mixture is extracted with ethyl acetate; the extract is filtered. washed to neturality. dried and evaporated. The product can be further purified by conventional techniques such as crystallization or chromatography.

Certain groups present in the starting compound of formula X are reduced by lithium aluminum hydride or diborane. For example. an acetyl group is reduced to an (ii-hydroxy ethyl group and a formyl group is reduced to a hydroxy methyl group. These reduced groups are regenerated after the completion of the first step of the above process via an oxidation process using manganese dioxide (active) in an inert organic solvent. such as acetone. petroleum ether. and the like. at about room temperature.

ln the second step of the above process. certain groups will he oxidized. For example. hydroxymcthyl and hydroxy groups will be oxidized. These groups can be advantageously protected by estcrifying these groups prior to the oxidation step of Scheme A. The groups can be regenerated after the above process by hydrolysis of the estcrified groups such as with an aqueous base. such as aqueous sodium carbonate.

The acctals of the compounds of formula Xl are prepared by treating the aldehyde products with alcohols. such as methanol. propanol. butanol. isopentanol. neopentanol. hexanol. isohcxanol. cyclopropanol. cyclobutanol. cyclopentanol. eyclobutylmethanol. cyclohexylmethanol. 2-cyclopropylethanol. 2-eyelohexylethanol. 3-cyclopropylpropanol. 3-eyclopentylpropanol. phenylmethanol. p-tolylmcthanol. 3-chlorophcnylmethanol. 3.5-dihydroxyphenylmethanol. 2.4-diethylphenylmethanol. 4-methoxyphenylmethanol. Z-phenylcthanol. 3-phenylpropanol. 1.2-butandiol. 1.3-butandiol. 1.4- butandiol. 2.3-butandiol. 1.2.4-butantriol. 2-n-butyl-2- ethyll .S-propancdiol. 2.2-dicthyll .3-propanediol. 2.2-diniethyl-l.B-propanediol. 2.2-diphcnyl-l.3- propanediol. 2-ethyl-l.3-hcxancdiol. 2-ethyl-2-methyll.3-propanediol. 2-methyl-2-propyl-l.3-propanediol. 1.2-pcntanediol. 2.3-pentanediol. 2.2-dimethyl-l.3- pentanediol. 3-mcthyl-2.4-pentancdiol. 2.3- hcxanediol. 3.4-hcxanediol. Z-ethyl-l.B-hexanediol. 3-methyl-2.4-heptanediol. 2.."i-octanediol. 4.5- ethyleneglycol. l.2-propanediol. 1.2- octanediol. 2.3-nonanediol. 4.5-nonancdiol. 1.2- dodccanediol. 2.3-dodecanediol. 6.7-dodecancdiol. l.2-dccanediol. cyclopentylcthyleneglycol. l.2-dicyclohcxylethyleneglycol. 3-cyclopropyl-l.2- propanediol. 1 cyclobutyl-2.3-hexanediol. 4-cyclopentyl-l.2-butancdiol. l.o-dicyclopentyl-4.5-hexanediol. l.3-dicyclopropyl-l ,2-propanediol. l-cyclopentyl-S- cyclohcxyl-2.Il-pentancdiol. 3-phenyl-l.Z-propanedlol. l-(4'-tolyl)-2.3-tridecancdiol. l-cyelohexyl-3-(2'- mcthoxy-hcnyl)-l.2-propancdiol. l-cyclopentyl-4-(3'-chlorophenyl)-2.3-butanediol. cyclopropyl-5-(4-hydroxyphenyl)-2.3-pentancdiol. l.4-di(2'. 6'-dimcthylphcnyl)-2.3-butancdiol. pehnylethylcneglycol, l-(4'-cthylphcnyl)-2.3-heptancdiol. tcyclohcxyl-Z-phcnylcthylencglycol. lcyclopcntyl-3- phenyl-Z.3-propanediol. l-cyclobutyl-4-(4'-isopropylphcnyl)-3.4-butancdiol. l,Il-diphcnyl-l.Z-propanediol. l.2-diphenylethylencglycol. l.3-propanediol. Z-methyl-l.J-propanetliol. 2-cyclohcxyl-l.3-propancdiol. 2- eyelopentylniethyhl.3-propanediol. 2-(2'- cyelopropylethyli-l.J-propanediol. 2-bcnzyl-l .3- propanediol 2-pltenyl-l..'i-propanediol. 2.2-dimethyl- IJ-propanediol. 2.2-diethyl-l.J-propunediol. 2.2-

- cyclohexylmethyl-4-benzyl-3.5-octanediol.

l0 dipropyl-l.3-propanediol.2.Z-dipentyl-l.3- propanediol. 2-methyl-2-ethyl-l.3-propanediol. 2- methyl-Z-propyl-l .3-propanediol. 2-cthyl-2-propyl- 1.3propanediol. 2-ethyl-2-butyl-l.3-propanediol. 2.2- dicyclopentyl-l.3-propanediol. 2.2-di(cyclohexylmethyl)-l.3-propanediol. 2-cyelohexylethyl-2-hexyl-l.3

propanediol. 2.2-dibenzyl-l.3-propanediol. 2.2- diphcnyl-l .3propanediol. 2-ethyl-2-t 3 '-tolyl )-l .3- propancdiol. 2-( 4'-methylbenzyl )-2-( 4'-tolyl l .3-

propanediol. 2.4-pentanediol. 3.5-heptanediol. 4.6- nonanediol. 2-ethyl-2-hutyll .S-propanediol. 2.2-diethyl-lJ-butanediol. Z-hexyl-Z-cyclohexyl-l.3hutanediol. 3-niethyl-2-cyclohcxyl-2.4-pentanediol. 2.2- di(cyclopropylmethyll-l.3-pentanediol. 3.3-dimethyl- 2.4-pentanediol. 3.3-diphenyl-2.4-pentanediol. 3.3-dihexyl-2.4-pentanediol. 3-methyl-3-phenyl-2.4- pentanediol. 3cyclopropyl-2.4-hexanediol. 2-(3'- ethylphenyl)-l.B-hexanediol. 3.3-dibenzyl- 2.4hexanediol. 3-(4-methoxyphenyl)-2.4-heptanediol. 4.4-diethyl-3.S-heptanediol. 4.4-dicyclohexyl-3.S-heptanediol. di(cyclohcxylethyl)-2.4-heptanediol. phenyl-3.S-heptanediol. octanediol.

3.3- 4-benzyl-4- 4-cyclobutylethyl-3.5- 4.4-dimethyl-3.S-octanediol. 4- 5- cyclopenylmethyl-4.ononanediol. 5.5-dipropyl-4.6- nonanediol. 5.5-dipcntyl-4.o-nonanediol. ethanol. 2- propanol. propanol. Z-pentanol. ethylene glycol. 1.2- propylene glycol. propane-l.3-diol. glycerine and the like. in the presence of an acid catalyst. such as p-toluenesulfonic acid. perchloric acid and the like.

The oxime derivatives of the compounds of formula Xl are prepared by refluxing the aldehyde product with hydroxylamine hydrochloride or monosubstituted hydroxylamine hydrochloride in the presence of pyridine in absolute ethanol to yield the corresponding oxime or l-monosubstituted oxyimino derivatives. The product is isolated by evaporating the reaction mixture. The product is further purified by crystallization or chromatography. Typical monosubstituted hydroxylamine hydrochloridcs used in the process include the hydrochloride salts of methoxyamine. butoxyamine. 2- butoxamine. pentoxyamine. 3--pentoxyamine. hexoxyamine. cyclopropoxyarninc. eyclobutoxyamine. ey clohcxoxy. cyclopentyl-methoxyamine. cyclohexylmethoxyaminc. 2-cyclopentylethoxyamine. Z-cyclohexylethoxyamine. cyclopropylethoxyamine. cyclobutylmethoxyaminc. benzyloxamine. Z-phenylethoxyamine. and the like. The hydrazone derivatives of the compounds offormula Xl are prepared by treating the aldehyde product with hydrazine in the presence of sulfuric acid or hydrochloric acid in methanol or ethanol. The semicarbazone derivatives of the compounds of formula Xl are prepared by heating the aldehyde products with an unsubstituted or substituted semicarbazide hydrochloride salt and sodium acetate in ethanol and water. The scmicarbazone. hydrazone and oxime derivatives of the compounds of formula Xl can be further purified by recrystallization from ethanol-water. When the 2-(2'-naphthyl) acetaldehyde derivative is substitutcd with an acetyl group. only 1.] molar equivalents of scmicarbazine hydrochloride. hydrazone or hydroxylaminc hydrochloride is employed and the product is purified hy ehromatographing on alumina or silica.

The hydroxy amino derivatives of the compounds of formula XI are prepared by treating the aldehyd pm\ acts with unhydrou mmonia as in an vent such as diethylether. The resulting hydroxy amino derivatives are isolated by filtration.

The bisulfitc addition derivatives of the compounds of formula Xl are prepared by treating the aldehyde products with a saturated aqueous solution of sodium bisulfite. The bisulfite addition derivatives can be purified by crystallization.

The unsubstituted and substituted imino derivatives of the compounds of formula Xl are prepared by treating the aldehyde product with anhydrous ammonia or a monosubstitute amine in a halogenated hydrocarbon solvent at a temperature of from about 70C to about 50C.. preferably at C to give the corresponding 1- (unsubstituted or substituted) arnino-2-(2'-naphthyl) ethanol derivative. The latter is heated between about C and 150C. preferably about 50C. under reduced pressure to yield the corresponding l-(unsubstituted or substitutedi-imino derivatives. Typical mono'substituted amines that are used include: methylamine. propylaminc. hexylamine. isopentylamine. cyclopropylamine. cyclobutylmethylamine. cyclopentylmethylamine. 2-cyclopropylethylamine. 2- cyelohexylcthylamine. benzylamine. 4'- methylbenzylamine. 2'.6-difluorobenzylamine. phenethylamino and the like.

When a resolved optical isomer of a 2-(2'-naphthyl) acetic acid starting compound of formula lX is employed in the above process. the corresponding resolved optical isomer of the compound of formula X is obtained.

The Z-(T-naphthyl) acetic acid starting materials of formula X are known and can be prepared by any one of several methods fully described in our co-pcnding U.S. application Ser. No. 608.997. filed Jan. l3.1967. now abandoned. No. 694.771. filed Dec. 7. 1967. now abandoned and No. 741.858. filed July 2. i968. now abandoned.

One method is to treat a l-tetralone. optionally substituted at position C-5.o.7 or 8. or disubstituted at position C-6 and C-5.7 or 8. sequentially with l an alkyl carbonate and an alkali metal hydride. (2) an alkali metal hydride and an a-haloacetic acid and (3) an aqueous mineral acid to obtain the corresponding 2- (carboxymcthylt-l-tetralonc. The latter is reduced with sodium borohydride to form the corresponding l.- 2.3.4-tetrahydro-l-hydroxy-2-naphthyl acetic acid; this resulting product is hydrogenolyzed with hydrogen in the presence of a hydrogenation catalyst, such as a palladium catalyst; the resulting product is estcrii'ied and then dchydrogenated with palladium on charcoal catalyst at about l80C to furnish the corresponding 2- naphthyl acetic acid ester derivative.

The starting compounds of formula X that are substituted at position C-l are prepared from the corresponding 2-(carbomcthoxymethyl)-l-tetralones by treating the latter l) with a phosphorous pentahallde to introduce a halo group at the C- 1 position or (2) with alkyl magnesium bromide and then with aqueous mineral acid to alkylate at the C-l position or (3) with trialkyl orthoformate in the presence of an acid catalyst to add an alkoxy group at position C-l and then dehydrogenating the resulting halogenated or alkylatcd or alkoxylated product by refluxing with 2.3-dichloro-5.(idicyano-l.4-benzoquinone. By employing substituted-2-(carbomcthoxymethyl)-l-tetralones in the above processes. the corresponding l-substitutcdo-substituted compounds of formula lX are prepared.

The starting compounds of formula lX substituted at position C4 or disubstituted at positions C-4 and o are prepared from unsubstituted and o-substituted S-(carbomethoxymcthyl) tetralones. respectively. via the processes used to prepare l-substituted-Z-naphthyl acetic acids from 2-(carboxymethyl) tetralones. 2(Carboxymethyl) tetraloncs are prepared via the process described in J. Chem. Soc. (London) i922. i717.

The Z-naphthyl acetic acid starting materials that are substituted at C5 or C-7 with a cycloalkyl. hydroxymethyl. alkoxymethyl. vinyl. ethynyl. formyl. acetal. or monocyclicalkyl group are prepared from the corresponding C-S or or, substituted ltetralones. which are prepared. by conventional methods or the methods de scribed in our copcnding U.S. application Ser. No. 694.77 I filed on Dec. 7. i967. employed in the preparation of l-tetralones. similarly substituted at or). For example. a S-methyl-l-tetralone is ketalized with ethylene glycol and p-toluenesulfonic acid and then treated with N-bromo succinimide to yield the corresponding S-bromomethyl derivative which is deketalized by acid hydrolysis. The S-bromomethyl compounds are treated with potassium acetate in dimethylformamide. and then hydrolyzed with aqueous base to yield the corresponding S-hydroxymcthyl l-tetralones. The 5- hydroxymethyl group is etherified by conventional means; such s treating the S-hydroxymethyil -tetralone with sodium hydride and methyl iodide to obtain the corresponding S-methoxymethyl-l-tetralone. The S-hydroxymethyl-l-tetralone is ltetalized and oxidized with manganese dioxide to yield the corresponding 5-formyl-l-tetralone ketal compound. When the latter is treated with methylmagnesium bromide the corresponding 5-(l'-methyl-l'hydroxymethylt-l-tetralone ketal is obtained. which when dehydrated with heat in the presence of acid yields the corresponding S-vinyl-ltetralone. The S-ethynyl-l-tetralone is prepared by treating the corresponding S-vinyl compound with a molar equivalent of bromine and then debrominating the resulting dibromo product with potassium hydroxide. The S-acetal-l-tetralone is prepared by oxidizing the 5-(l'-methyl-l-hydroxymethyl)-l-tetralone with chromium trioxide in 8N sulfuric acid. The S-cycloalkyl-l-tetralone is prepared by treating the corresponding S-chloro-ltctralone with ethylene glycol and p-toluene-sulfonic acid and then with magnesium in tetrahydrofuran to yield the corresponding Grignard reagent; this in turn is treated with the corresponding oxoalkyl. such as cyclohexanone. to obtain the corresponding 5-(l'-hydroxycycloalkyl)-l-tetralone ketal. The latter is acid hydrolyzed and then hydrogenolyzed with a molar equivalent of hydrogen in the presence of Raney Nickel to yield the corresponding S-cycloalkyl compound. The S-aryl-l-tetrulones can be prepared by treating l-tetralon-S-yl magnesium chloride ketal. prepared as described above. with an unsubstituted or substituted cyclohexenone in tetrahydrofuran to yield the corresponding S-(unsubstituted or substituted) cyclohexadienyl-i-tetralone ketal. which upon a mild dehydrogenation in the presence of 5% palladium on charcoal at about lC and acid hydrolysis yields the corresponding S-(unsubstituted or substitutedi-phenyll-tetralone. Similarly. the 7-substituted-l-tctralones can be prepared from 7-methyl-l-tetralone and 7- ehloroor 7-bromo-l-tetraione by means of the above described processes.

The disubstituted 2-(2'-naphthyl) acetic acid deriva tives of formula X are prepared by the methods disclosed in our copendiug US. application Ser. No. 606,997, filed Jan. i3, 196?. now abandoned; Ser. No. 694,77l filed Dec. 7, 1967. now abandoned and Ser. No. 741,858 filed July 2. i968. now abandoned. For example. 2-(5',6'-disubstituted-2'-naphthyl) acetic acid derivatives are prepared by treating methyl phenylacetate with at least 2 molar equivalents of a 2- substituted succinic anhydride. such as 2-methoxy succinic anhydride, and at least 2 molar equivalents of aluminum chloride in nitrobenzcnc or carbon disulfidc to yield the corresponding methyl p-(3'-carboxy-3'- substituted-l 'oxopropyl) phenyl acetate and methyl p-(3'-carboxy-2 substitutedl '-oxypropyl) phenyl acetate derivatives. The derivatives are separated by conventional means. such as by chromatography or distillation. The loxo group of the 2'-substituted derivative is selectively reduced with sodium borohydride to a lhydroxy group. The l'-hydroxy derivative is esterified by treatment with acetic anhydride in pyridine. The re suiting l'-acetoxy derivative is treated with thionyl chloride, phosphorus trichloridc or phosphorus pentachioride to yield the corresponding methyl p-(3'-chlorocarbonyl-2-substitutedl '-acetoxypropyl) phenyl acetate derivative. which when treated with at least 3 molar equivalents of aluminum chloride in benzene yields the corresponding 7-carbomethoxymethyl-4-acetoxy-J-substitutcdl-tctralone,which is selectively reduced with sodium borohydride to give the corresponding methyl 2-(5'-acetoxy-6-substituted-W-hydroxy-S'.6'.7'.8'- tetrahydro-Z'-naphthyl) acetate. The latter is esterificd with acetic anhydride and pyridine and selectively hydrogcnolyzed with a molarcquivalent ofhydrogcn in the presence of a palladium catalyst to yield methyl 2-(5-acetoxy-6'-substituted-5',6,7,8'-tetrahydro-2'- naphthyl) acetate derivative, which is hydrolyzed with aqueous base, such as with 5% aqueous sodium bicarbonate solution, and csterified with diazomethane to yield the corresponding methyl 2-(5-hydroxy-6- substituted-5',6,7',8'-tetrahydro-2'-naphthyl) acetate derivative. The latter is treated with at least 2 molar equivalents of N, N-diethyl-N-(l,l,2-trifluoro-2- chloroethyl) amine in methylene chloride and then it is refluxed with 2.3-dichloro-5.-dicyano-l,4- bcnzoquinonc in xylene to yield the corresponding methyl 2-(5-fluoro-6'-substitutcd-2'-naphthyl) acctate. The 5'-hydroxy derivative is heated with a thioalkane in the presence of acid at about 180C in a sealed container to yield the corresponding methyl 2-(5'- alkylthio-6-substitutcd-2-nuphthyl) acetate. The 5'- hydroxy derivative is oxidized with chromium trioxidc in acetic acid to yield the corresponding methyl 2-(5- oxo-6-substitutcd-2'-naphthyl) acetate derivative. The 5-oxo derivative is treated with phosphorus pentachloride and then refluxed in 2,3-dichloro-5,6-dicyano-l ,4- bcnzoquinone in xyleneto yield the corresponding 2-(5 -ehloro 6'-siibstituted-2'-naphthyl) acetic acid. The 5'-chloro derivative is refluxed with cuprous bromidc in dimcthylsulfoxide to yield the corresponding methyl 2 iS bro mo 5'-subs tituted 2" iia ph thyli ace tatc derivative; by employing cuprous iodide in place of cuprous bromide, the corresponding 5-iodo derivative is obtained. The 5-oxo derivative is treated with at least a molar equivalent of an alkyl magnesium bromide. then acid hydrolyzed and finally heated with 5%- palladium on charcoal to about l8tlC to yield the cor- -rcsponding 2-(5'-all yl-6'-substituted-2'-naphthyl) 5 acetic acid. The 5'-oxo derivative is treated with trialkyl orthoformate in the presence of an acid catalyst, such as p toluenesulfonic acid in an aryl hydrocarbon solvent, and then it is refluxed with DDO in xylene to y e dth s sesnd s restful. 2.1!..5'1t ktt16 substituted-2'-naphthyl) acetate derivativeThe 3-substituted-l'-oxo derivative. prepared as described above, is selectively reduced with sodium borohydride, treated with thionyl chloride or the like, treated with aluminum chloride in benzene, esterified with acetyl chloride, selectively reduced with sodium borohydride, dchydrogenolyzed, and hydrolyzed with aqueous base, 115 described above 9 el thssprrssno d ns me hyl 2-(5'-hydroxy-7-substitutcd-5Co.7'.8-tetrahydro-2'- naphthyl) acetic derivative. The latter is treated as described above to dehydrogenate and introduce the C-' fluoro, chloro, bromo, alkyl, alkoxy and alkylthio groups.

The compounds of formula X substituted at the 2 position are prepared from the corresponding 2- unsubstituted compounds of formula X by csterifying the latter, and treating it with ethyl formate and sodium metal to obtain the corresponding 2.2- hydroxymcthylene derivative. The latter is treated with sodium hydride. then with chlorine gas, then with chromium trioxide in acetic acid and then heated to yield the corresponding 2 -chloro derivative. The 2(2- chloro-2-naphthyl) acetic acid derivative is refluxed in sodium hydroxide, esterificd with diazomcthanc, oxidized with chromium trioxide in acetic acid and coupled by refluxing with difluoromethylenc triphenyi phosphorane in benzene to obtain the corresponding 2,2-difluoromethylene derivatives of formula lX.

The Z-methyl substituents are added to the 2- unsubstituted compounds of formula X by esterifying the latter and treating it with sodium hydride and alkyl halide, such as methyl iodide. The Z-difluormethyl substitucnt is added by treating the 2-unsubstituted compounds of formula X successively with sodium hydride and diethyl carbonate, then with chlorodifluoromethane, then with aqueous 5% sodium hydroxide at 75C followed by acidification with aqueous mineral acid and then finally heating the resulting product to about l50C to yield the corresponding Z-difluoromethyl derivatives of formula X.

The 2,2-methylenc substituents are introduced by treating the 2-unsubstituted compounds of formula X with formaldehyde and an alkali metal hydroxide. The 2,2-cthylenc suhstituents are introduced by refluxing the corresponding 2,2 methylene derivatives of formula X with diiodomcthanc in the presence of zinccopper couple.

The various substituted tctralones are known and can be prepared by conventional methods. For example, the 5,7-disubstitutcd tetralones are prepared by treating a l,3-disubstituted benzene derivatives with 2 or more molar equivalents of succinic anhydride and two or more molar equivalents of aluminum chloride in nitro benzene or carbon disulfide to obtain the correspending 4-0x0-4-t2',4'-disubstitutcd phenyl) butyric acids. Thclattcr are reduced with a reducing agent such as sodium borohydride or one molar equivalent of hydrogen in the presence of platinum to reduce the tained. The compounds are separated by conventional techniques. such as distillation or chromotagrophy, including gas-liquid chromatography.

The 2-naphthyl acetic acids of formula X that exist as enantiomorphs can be resolved by preparing the alkaloid base salts of the latter. resolving the resulting diastero-isomer salts by fractional crystallization and cleaving the resolved salts. The optical rotation of a particular Z-naphthyl acetic acid is determined by polarimetry.

The following examples are included to further illustrate the present invention and are not intended as limitations of the present invention.

PREPARATlON l A mixture of 1925 g. of l-chloro-2- mcthoxynaphthalene. 80 g. ofacetyl chloride, 400 g. of aluminum chloride and 2.5 liters of nitrobenzene are stirred for 60 hours at room temperature. The resulting mixture is then washed with dilute hydrochloric acid. dried over sodium sulfate and evaporated to yield 2- acetyl-5-chloro-(i-methoxynaphthalene. The resulting acctyl p oduct is added to a mixture of 39 g. of sulfur and l05 g. of morpholine and heated to about 150C for 3 hours. The mixture is then added to l liter of concentrated hydrochloric acid and refluxed for 3 hours. The mixture is then cooled. diluted with 6 liters of icewater and extracted with methylene chloride. The extracts are combined. washed with water to neutrality. dried over sodium sulfate and evaporated to yield 2- t5'-chloro-6'-methoxy-2'-naphthyl) acetic acid.

In a similar manner.

2-(5'.o'-dimethyl-2'-naphthyl) acetic acid.

2-(5'-hromo-fi-methoxy-2'-naphthyl) acetic acid.

2-(5'-iodo-6-methoxy-2-naphthyl) acetic acid.

2-(5'.6-dimethoxy-2'-naphthyl) acetic acid. v

2-(5'-methylthio-6-chloro-2'-naphthyl) acetic acid.

and

2-(5-fluoro-6'-methoxy-2'-naphthyl) acetic acid,

are prepared from the corresponding 1.2- disubstituted naphthalenes by means of the above described process.

To a mixture of 50 g. of 2-(5'-chloro-6'-methoxy-2'- naphthyl) acetic acid and 250 ml. of diethyl ether. there are added 9 g. ofdiazomcthane in 250 ml. ofdiethyl ether. The mixture is stirred for l hour and then flushed with nitrogen gas until colorless. The mixture is then evaporated to yield methyl 2-(5'-chloro-6- methoxy-2'-naphthyl) acetate.

To a mixture of 4.8 g. of sodium hydride in 100 ml. of l.2-dimcthoxyethane. there are added 53 g. of the above methyl ester product. The mixture is stirred for 2 hours; then I) g. of methylbromide in 200 ml. of l.2- dimethoxyethane are slowly added. The resulting mixpropionaldehyde.

ture is stirred for 3 hours at 25C; it is then diluted with l l. of ice-water and extracted with diethyl ether. The extracts are combined. washed with water. dried over sodium sulfate and evaporated to yield methyl 2-(5'- chlor0-6'-methoxy-2'-naphthyl) propionate.

EXAMPLE l To a mixture of 0.4 g. of lithium aluminum hydride and I00 ml. of ethyl ether. a mixture of 2.3 g. ofd and l 2-(6'-methoxy-2'-naphthyl) propionic acid and I00 ml. of ethyl ether. The mixture is stirred at 0C for 30 minutes. then it) ml. of ethyl acetate are added; l hour later 18.5 ml. of water are added. The resulting mixture is filtered and evaporated under reduced pressure. The resulting residue is added to a mixture of IO g. of chromium trioxide and l liter of pyridine. The resulting reaction mixture is stirred under anhydrous conditions for 24 hours at 25C. then 1 liter of ethyl acetate is added. The result ethyl acetate mixture is filtered. washed with an aqueous saturated solution of sodium bisulfite and water to neutrality, dried over sodium sulfate and evaporated under reduced pressure to yield a racemic micture of 2-t6'-methoxy-2'-naphthyl)- propionaldehyde.

By employing a resolved 2-(2-naphthyl) acetic acid derivative in the above process. the corresponding 2- (2'-naphthyl) acid aldehyde derivatives will be obtained. For example. if R 2-(6-methoxy-2'-naphthyl)- propionaldehyde is prepared from R 2-(6'-methoxy-2'- naphthyl)propionic acid and S 2-(6'-methoxy-2'- naphthyl) propionaldehyde is prepared front S 2-(6'- methoxy-2'-naphthyl)propionic acid [these compounds have been named in accordance with the Cahnlngold-Prelog system of naming optical isomers; see R.S. Cahn. C.K. lngold and V. Prelog. "Experiential". Vol. l2. 81-95 i956) and Carl R. Noller. Chemistry of Organic Compounds. pp. 368-370, W.B. Saunders Co.. Philadelphia l965)].

Similarly. 2-( l '-trifluoromethyl-2'-naphthyl)- 2-(4'-fluoro-2'-naphthyl)-butanal. 2-(5'-methoxy-2'-naphthyl)-propionaldehyde. 2-(5'- methyl-2'-naphthyl)-acetaldehyde. 2-(5'-chloro-2'- naphthyl)-propionaldehyde. 2-(5-methylthio-2'-naphthyl)-2.Z-methylacetaldehyde. 2-(6-methylthio-2- naphthyl)-2-difluoromcthyl acetaldehyde. 2-(6'- methoxy-2'-naphthyl)-2-difluoromethyl acetaldehyde. 2-(6'-methyl-2'-naphthyli-propionaldehyde. 2-(6'- ethynyl-2'-naphthyl )-propionaldehyde. 2-(o'-acetyl-2'- naphthyl)-2.2-methylcne acetaldehyde. 2-(6'-chloro- 2'-naphthyl)-propionaldehyde. 2(7'-methyl-2'-naphthyl)-propionaldehyde. 2-(7'-methoxy-2'-naphthyl)- acetaldehyde. 2-(7-chloro-2'-naphthyl)-propionaldehyde. 2-(7'-methylthio-2'-naphthyl)-2,2-methylene acetaldehyde, 2-(8'-ethylthio-2'-naphthyl)-butanal. 2-(5 chloro-6'-methoxy-2'-naphthyl)acetaldehyde. 2-(5- chloro-6'-methoxy-2-naphthyl) propionaldehyde. 2- (5-bromo-6'-methoxy-2'-naphthyl) propionaldehyde. 2-(5'.7'-diehloro-2'-naphthyl)-aeetaldehyde.

2-( l -fluoro- 6'-methoxy-2'-naphthyll-propionaldehyde and 2- (5.7'-dimethyl-2'-naphthyl) propionaldehyde are prepared from the corresponding substituted 2-na ilttliyl acetic acids.

acetic acid. 57 g. of lithium aluminum hydride and 10 liters of tetrahydrofuran is stirred for 2 hours at C. then l liter of ethyl acetate is added. After one hour 500 ml. of water is added to the resulting mixture. the mixture is stirred. filtered. dried over sodium sulfate and evaporated under vacuum. The residue is added to a mixture of 620 g. of dicyclohcxyl carbodiimide. 50 g. of anhydrous phosphoric acid and 2 liters of dimethylsulfoxide. The resulting mixture is stirred for 8 hours. then added to water. filtered to remove dicyclohexyl urea and extracted with ether. The combined ether extracts are filtered. washed with water to neutrality. dried over sodium sulfate and evaporated to yield 2-(5-methoxy-2'-naphthyl) acetaldehyde.

Similarly. 2-( l '-methoxy-2'-naphthyl) acetaldehyde. 2-(4'-rlifluoromethylthio-2'-naphthyl) dehyde. 2-(5'-fluoro-2-naphthyl) acetaldehyde. Z-t5'methylthio-2'-naphthyl) propionaldehyde. 2-(5'-chloro-2'-naphthyl) acetaldehyde. 2-(5-trifluoromethyl-2'-naphthyl)-2.2-

difluoromcthylene acetaldehyde. 2 (6'-fluoro-2'-naphthyl) propionaldehyde. 2-(6'-methyl-2"naphthyl) acetaldehyde. 2-(6'-mcthoxy-2'-naphthyl) acetaldehyde. 2-(6-diiiuoromethoxy-Z-naphthyl)-2- difluoromethyl acetaldehyde. 2-(6"difluoromethoxy-2'-naphthyl) acetaldehyde. 2-(6'-methoxy-2'-naphthyl) butanal. 2-(7'-fluoro-2-naphthyl)-2-propionaldehydc. 2-(7'-vinyl-2'-naphthyl)-2-propionaldehyde. 2-(7-methylthio-2'-naphthyl)-2-butanal.

2-(7'-mcthylthio-2'-naphthyl) acetaldehyde. 2-(7'-chloro-2'-naphthyl)-2.2-methylenc acetaldehydc. 2-(8'-trifluoromethyl-2'-naphthyl)-2.2-methylenc acetaldehyde. 2-(5.7'-dimethoxy-2'-naphthyl) propionaldehyde. 2-(5'.6-dimethyl-2'-naphthyl) propionaldehyde. and

2-(5'-bromo-6'-methoxy-2-naphthyll propionaldehyde are prepared. respectively. from the corresponding compounds by means of the above process: 2-(l'-metlioxy-2'-naphthyl) acetic acid. 2-(4'-difluoromcthylthio-2'-naphthyl) acid. 2-(5'-fluoro-2'-naphthyl) acetic acid. 2-(5'-methylthio-2-naphthyl) propionic acid. 2-(5'-chloro-2'-naphthyl) acetic acid. 2-(5'-trifiuoromethyl-2'-naphthyl)-2.2-

difluoromethylene acetic acid. 2-(6'-fluoro-2-naphthyl) propionic acid. 2-(6'-methyl-2-naphthyl) acetic acid. 2-(6-methoxy-2'-naphthyl) acetic acid. 2-(6'-difluoromethoxy-2'-naphthyl)-2- difluoromethyl acetic acid. 2-(6'-difluoromethoxy-2'-naphthyl) acetic acid. 2-(6-methoxy-2'-naphthyl) butyerie acid. 2-(7'-fluoro-2-naphthyl) propionic acid. 2-(7-vinyl-2-naphthyl) propionic acid. 2 (7'-methylthio-2-napthyl) butyeric acid. 2-(7-methylthio-2'-naphthyl) acetic acid. 2-(7'--chloro-2'-naphthyl)-2.2-methylenc acetic acid. 2-(8'-triflaoromethyl-2-naphthyl)-2.2-methylene acetic acid. 2-(5'.7-dimethoxy-2-naphthyl) propionic acid.

propionalpropionic 2-(S'.6'-dimethyl-2'-naphthyl) propionic acid. and 2-(5'-bromo-6'-methoxy-2'-naphthyl) propionic acid. respectively. by means of the above process.

EXAMPLE 3 A mixture of 46 g. of 2-(7'-methoxy-2'-naphthyll propionic acid. in 200 ml. of tetrahydrofuran is treated with 6 g. ofdihorane in 500 ml. of tetrahydrofuran and stirred for l hour at room temperature (about 23C). The mixture is allowed to stand forone hour after being diluted with ml. of aqueous acetone. thel l liter of diethyl ether are added. The resulting mixture is washed with water. dried over sodium sulfate and evaporated. The resulting residue is added to a mixture is stirred under anhydrous conditions for 24 hours at 25C; then l liter ofethyl acetate is added. The mixture is then filtered. washed with an aqueous acidified solution of sodium bisulfite and water to neutrality. dried over sodium sulfate and evaporated under reduced pressure to yield 2-(7-methoxy-2'-naphthyl) propionaldehyde.

Similarly.

2-(5'-methyl-2'-naphthyl) propionaldehyde.

2-(5-difluoromethoxy-2'-naphthyl) propionaldehyde.

2-(5-difluoromethoxy-2'-naphthyl) acetaldehyde.

2-(5'-methylthio-2'-naphthyl) acetaldehyde.

2-(6'-ethyl-2'-naphthyl) propionaldehyde.

2-(6'-chloro-2'-naphthyl)- 2-difluoromethyl acetaldehyde.

2-(6'-vinyl-2'-naphthyl)-2.2-methylenc hyde.

2-(6'-methylthio-2'-naphthyl) acetaldehyde.

2-(6'-trifluoromethyl-2'-naphthyl) acetaldehyde. 2-

(7'-cyelopropyl-2'-naphthyl) propionaldehyde. 2-(7'-acetyl-2'-naphthyl) propionaldehyde. 2-(7'-fluoro-2'-naphthyl) acetaldehyde. 2-(7'-trifluoromethyl-2'-naphthyl) propionaldehyde.

acetalde- 2-( l '-chloro-2'-naphthyl) butyrylaldehyde. 2-(4'-ethoxy-2-naphthyl)-2.2-ethylene hyde. 2-(6'.7 -dimethoxy-2'-naphthyl) propionaldehyde. 2-(5.7-dimethyl-2'-naphthyl) acetaldehyde. and 2-(8'-methoxy-2'-naphthyl) propionaldehyde.

prepared from 2-(5'-methyl-2'-naphthyl) propionic acid. 2-(5'-diflu0romethoxy-2'-naphthyl) propionic acid. 2-(5'-difluoromethoxy-2'-naphthyl) acetic acid. 2-(5'-methylthio-2'-naphthyl) acetic acid. 2-(6'-ethyl-2'-naphthyl) propionic acid. 2-(6'-chloro-2'-naphthyl)-2-difluoromethyl acid. 2-(6'-vinyl2'-naphthyl)-2.2-methylene acetic acid. 2-(6'-methylthio-2-naphthyl) acetic acid. 2-(6'-trifluoromethyl-2'-naphthyl) acetic acid. 2-(7-cyclopropyl-2'-naphthyl) propionic acid. 2-(7'-acetyl-2-naphthyl) propionic acid. 2-(7'-fluoro-2-naphthyl) acetic acid. 2-(7'-trifluoromethyl-2'-naphthyl) propionic acid. 2-( l '-ehloro-2-naphthyl) butyric acid. 2-(2'-ethoxy-2'-naphthyl)-2.2-ethylene acetic acid. 2-(6.7'-dimcthoxy-2'-naphthyl) propionic acid. 2(5'.7'-dimethyl-2'-naphthyl) acetic acid. and 2'-(8'-mcthoxy-2'-naphthyl) propionic acid. respectively. by means of the above process.

acetaldeacetic 0.8 g. of p-toluenesulfonic acid monohydrate is refluxed for l2 hours with a water trap. Aqueous sodium bicarbonate solution is then added to the cooled mixture and the organic phase is separated. washed with water. dried over anhydrous sodium sulfate and evaporated to dryness to yield ethylcnedioxy 2-ti' methoxy- 2'-naphthyl) ethane which is recrystallized from tree tone: hexane.

Similarly. by employing glycerine. 2.3- dihydroxybutane. 2.2-dimethyl-l.3-dihydroxypropane. 2.2-diethyl-l.B-dihydroxypropane. 2.2-diphenyl-l.3- dihytlroxypropane. 2.2-dicyclopentyl dihydroxypropane. 2-cyclohexylmethyl-l.3 dihydroxypropane. 2- ethyl-2-(2'-cyclopropylethyl)-l,3-dihydroxypropanc. l.3 -dihydroxypropanc. 3.4-dihydroxyhexane. 2.3- dihytlroxynonane and 2.4-dihydroxpentane in place of ethylene glycol in the above process. the corresponding glycerol. i')Ul't\l\C-1.3-(llUX)'. 2.2-dimethylpropane-l.3- dioxy. 2.2-diethylpropane-l.B-dioxy. 2.2-diphenylpropane-1.3-dioxy. 2.2-dicyclopentylpropane-l.3-dioxy. 2-cyclohexylmethylpropane-l.l-dioxy. 2-ethyl-2-(2'- cyclopropylethyl lpropanc l .3-dioxy. propanel .3- dioxy. hexane-3.4-dioxy. nonaneZJdioxy. and pentane-2A-dioxy cyclic acetals oi 2-(5'-methoxy-2'- naphthyl) acetaltlehyde. respectively. are obtained.

By employing the 2-(2'-naphthyl) acetaldehyde derivatives prepared in Examples 1. 2. 3 and 4 in the above process. the corresponding ethylenedioxy cyclic acetals thereof are obtained.

EXAMPLE (1 A mixture of 2| g. of 2-(6-methoxy-2-naphthyl) propionaldehyde. 500 ml. of ethanol and 20 drops ol perchloric acid are allowed to stand for eight hours at room tentperature under anhydrous conditions The mixture is then diluted with 500 ml. of aqueous 1% sodium bicarbonate; and extracted with methylene chloride. The cotnbined extracts are washed with water to neutrality. dried over magnesium sulfate and evaporated to yield l.l-diethoxy-2-(6'-niethoxy-2'-naphthyl) propane.

l.l-Dimethoxy-2-(6'-methoxy-2-naphthyl) propane. l,l-dipropoxy-2-(o'-methoxy-2'-naphthyl) propane. l.l-diisopropoxy-2-t( '-mcthoxy-Z'maphthyl) propane. l.l-dipentoxy-2-( o'-methoxy-2-naphthyll propane. l .l;dicyclopropoxy-2-((1'-methoxy-2'- EXAMPLE 7 Water is added to a solution of 2().l g. of 2-(6'- methoxy-2'-naphthy|) acetaldehyde and 500 ml. ofcthanol until the solution is faintly turbid; the turbidity is removed by the addition of several drops ofethanol. To this resulting solution then is added 25 g. of semicarbatide hydrogenehloride and 50 g. of sodium acetate. The

resulting mixture is refluxed for l minutes and then is allowed to cool at 0C for 24 hours. The cooled mixture is then filtered and the resulting crystals are washed with several protions of ice cold ethanol to yield the semicarbazone of 2-(6'-methoxy-2'-naphthyl) acetaldehyde. The semicarbazone is recrystallized from waterzethanol (3:1).

ln a similar manner. the semicarbazones of the 2-( 2'- naphthyl) acetaldehyde derivatives oi Examples l. 2. 3 and 4 are prepared by means of the above process. For example. the semicarbazone of 2-(5' methoxy-2- naphthyl) acetaldehyde is prepared by employing 2-tS'-methoxy-2'-naphthyl) acetaldehydc in the above process.

EXAMPLE 8 A mixture of 50 g. of 2-( 5'-methoxy-2'-naphthyl) acetaldehyde. 50 g of hydroxylamine hydrogenchloride. 500 ml. of pyridine and 500 ml. of absolute ethanol are refluxed for 8 hoursv The resulting mixture is cooled and evaporated under reduced pressure. The resulting residue is triturated with 250 ml. of cool water; the resulting aqueous mixture is then filtered. The resulting crystals are washed thoroughly with several portions of water to yield 2-(S-methoxy-2'-naphthyl) acetalodime. Similarly. by employing the 2-(2'-naphthyl) acetaldehyde derivatives prepared in Examples 1. 2. 3 and 4 in the above process. the corresponding oxime derivatives thereof can be obtained. For example. 2-( 5'methyl-2-naphthyll acetaldoxime is prepared by using 2(5' methyl-2'-naphthyll acetaldehyde in the above process.

lMeth0xyimino-2-(6'-methoxy-2'-naphthyl) ethane. l-ethoxy-imino-2-(o'-methoxy-2'-naphthyl) ethane. l-i-propoxyimino-2-(6'-methoxy-2-naphthyl) ethane & l-benzyloxyimino-2-(6'-methoxy-2'-naphthyl) ethane. are prepared by employing methoxyamine. ethoxyaminc. i-propoxyamine and benzyloxyaminc'. respectively. in place of hydroxylamine in the above described process.

EXAMPLE 9 A mixture of 20! g. of 2-(7-methyl-2'-naphthyl) acetaldehyde. 200 g. of acetic anhydride. 68 g. of borontrifluoride are stirred for 8 hours at about 5C. The resulting reaction mixture is evaporated under reduced pressure to yield 2-(7'-methyl-2'-naphthyl) ethylidenediacetate.

in a similar manner. the acylals of the 2-(2'- naphthyl) acctaldehyde derivatives prepared in Examples l. 2. 3 and 4 are prepared by means of the above described process. For example. 2-(5'-methylthio-2'- naphthyl) ethylidenediacetate is prepared from 2-(5'- methylthio 2'-naphthyl) acetaldehyde by means of the above process.

2-(5'-Methoxy-2'-naphthyl) ethylidenedipropionate. 2-(5-methoxy-2'-naphthyl) ethylidenedieaproatc. 2-(5'-methoxy-2'-naphthyl) ethylidenedivalerate. and 2-(5'-methoxy-2'-naphthyl) ethylidenesuccinate are prepared by utilizing propionie anhydride. eaproic anhydride. valeric anhydride and suceinic anhydride. respcctively. in place of acetic anhydride in the above described process.

EXAMPLE 10 To a refluxing mixture of 18.5 g. of 2-(7'-methylthio- 2-naphthyl) propionaldehyde. l8.5 gv ofhydrazine and 350 ml. of ethanol. there is added drops of glacial acetic acid. The mixture is refluxed for an additional 5 minutes and sufficient ethanol is added to obtain a clear refluxing solution. The solution is cooled and liltered. The resulting crystals are thoroughly washed with cold (0C) ethanol. The crystals are recrystallized from ethanol to yield the hydrazone or 2-(7'-methylthio-T-naphthyl) propionaldehyde.

Similarly. the hydrazones ol'the 2'( 2'-naphthyl acetaldehyde derivatives of Examples l.2. 3 and 4 are prepared by means ofthe above described process. For example. the hydra/one ol' 2-t 4'-chloro-2'-naphthyl)-2.2- methyleneacetaldehytle is prepared is prepared from 2-(4'-ehloro-2'-naphthyl)-2.2-methylene acetaldehyde by means of the above described process.

Part A A mixture of 2L5 g. of 2-(t'i'-methoxy-2'- naphthyll propionaldehyde and Still ml. of methylene chloride are cooled to 0C and saturated with anhydrous ammonia. The mixture is stirred lor 12 hours while maintaining the temperature at 0C and continuing to bubble in ammonia. The resulting reaction mixture is then evaporated to yield l-amino-2-(6'- methoxy-2'-naphthyl) propanol.

Part B The above product is warmed to 50C under vacuum for 8 hours to yield l-imino-2-(6'-methoxy-2- naphthyl) propane.

ln :1 similar manner. the amino alcohols and aldi' mines of the 2-(2'-na .ihthyl) acetaldehyde derivatives of Examples l. 2. 3 and 4 are prepared by means of the above described process. For example. l-imino-2-t l ethyl-2'-naphthyl)-2.2-dilTuoromethyletie-ethane is prepared from l-amino-2-t l'-ethyl'2'-naphthyl)2.2- dilluoromethyleneethanol by means of the process described in Part [3 above. and l-amino-2-(l'-ethyl-2'- naphthylL2.2-dilluoromethyleneethanol is prepared from 2-( l -ethyl-2'-naphthyl)-2.2-dilluoromethylene acctaldehyde by means of the above process described in Part A described above.

l-Methylamino 2-(o'-methoxy-2'-naphthyl) propanol. l-ethylamino-2-((i'-mcthoxy-2'-naphthyl) propanol. l-i-propylamino 2-(6'-methoxy-2'-naphthyl) propanol. l-benzylamino-2-(6'-methoxy-2'-naphthyl) propane] and lphenylamino-2-(6'-methoxy-2'-naphthyl) propanol are prepared by employing mcthylaminc. ethylamine. isopropylaminc. benzylamine. and phenylamine. respectively, in place of ammonia in the process described above in Part A. By employing the thus prepared alkyl-. aralltyland arylamino-2-(6'-methoxy-2- naphthyl) propanols in the process described above in Part B. l-methylimino-2-(6'-methoxy-2'-naphthyl) propane. l-ethylimino-2-(o'-methoxy-2-naphthyl) propane. l-i-propylimino 2-(6'-methoxy-2'-naphthyl) propane. I-benzylimino-2-(6'-mcthoxy-2'-naphthyl) propane and l-phenylimino-2-(o'-mcthoxy-2'- naphthyl) propane. respectively. are obtained.

EXAMPLE l2 To 600 ml. of a 40% solution of sodium lJlSUlfitC. is added I ml. ofethanol and lOt) g. of 2-(6'-methoxy- 2'-naphthyl) propionaldehyde in 500 ml. of ether. The resulting mixture is stirred for 3 hours; then it is filtered to yield the sodium bisulfite addition product of 2-(6'- meth0xy-2'-naphthyl) propionaldchyde.

Similarly. the 2-(2'-naphthyl) acetaldehyde derivatives prepared in Examples 1. 2. 3 and 4 are employed in the above process to prepare the corresponding so dium bisulfite addition products thereof. For example. the sodium bisulfite addition product of 2-t 5'-methosy 2'-naphthyl) acetaldehyde is obtained by using 245'- methoxy-2'-naphthyli aeetaldehyde in the above process.

EXAMPLE l3 To a mixture of 50 g. of borontribron'iide in 250 ml. of methylene chloride. cooled to -8tlC. there is added 2L4 g. of 2 t6'-methoxy-2'-naphthyll propionaldehyde. The mixture is allowed to warm to room temeprature over l hour. The reaction mixture is then diluted with 250 ml. of water and filtered; the organic layer is then separated off. The organic layer is washed with water to neutrality. dried over sodium sulfate and evaportated to yield 2-t6'-hydroxy-2'-naphthyl) propionaldehyde.

By employing 2-t6'-methylthio-2'-naphthyl) acetaldehyde in the above process. 2-(o'-thio-2'-naphthyl) acetaldehyde is obtained.

Similarly. the methoxy. methoxymethyloxy. difluoromethoxy. methylthio. methoxymethylthio or difluoromethylthio substituted 2-(2'-naphthyl) acetaldehyde derivatives of Examples l. 2. 3 and 4 are employed in the above process. give the corresponding hydroxy or thin substituted 2(2'-naphthyl) accetalkdehyde derivatives. For example. 2-( 5'-thio-2'-naphthyl 2.2-methyleneacetaldehyde is prepared from 2-(5'- isopropylthio-Z'-naphthyll-2.2-methyleneacetaldehyde by means of the above process.

EXAMPLE l4 No of Dose Range Relative Potency to Rats Tested nig/Rat Phcnylhutaronc (Phenylbuuuone I) 3. ll.l 0.9 4

EXAMPLE l5 The analgesic activity of the bisulfite addition product of 2-(6'-methoxy-2'-naphthyl) propionaldehyde was compared with that of aspirin and phenylbutazonc. The test used was based on the test of Randall of Selitto. Arch. Int. Pharmaeodyn l ll. 409-419 (1957) and consisted of administering orally by gavage 30 or mg. per kilogram of body weight. the analgesic compound with water (20 ml. per kilogram of body weight) in eight male rats weighing between to 200 grams. A control group received an equivalent volume of water. One hour after the administeration of the compo-aid. lt) ml. of a 20% yeast suspension (Red Star Brand. primary dry type 600 in 0.9% saline) was injected into the subplantar area of the left hind paw of each rat in the drug treated group and the control group. The purpose of the injection is to provoke the formation of inflammatory edema.

Two hours after the injection of yeast. the control paw and the yeast inflammed paw of each rat in the drig treated group and in the control group successively were compressed at the plantar surface by a stud with a surface area of about mm. attached to a force displacement transducer (model PTO Grass) which was driven at a constant rate. The induced pressure was recorded on a strip Chart recorder. When a pain reaction was evoked from the rat by the application of pressure. the amount of pressure was recorded; the pressure was recorded in paper pressure units l00). The differ ence between the amount of pressure required to evoke pain reaction between the control paw and inflatnmed paw among the drug treated group of rats and control group of rats serves as an index of analgesic activity. The measure of analgesic activity in the rats is ex pressed in percent. in reference to that of the inflammed paw and non-inflammed paw. [(Pressurc units to evoke pain in inflammed paw/pressure units to evoke pain in control paw) or l00 l. The results are summarized in the following table.

Degree of Analgesic in percent with Reference to the (oniroh EXAMPLE to The analgesic activity of several 2-t2-naphthyl) acetaldehyde derivatives was compared with that of aspirin and phenylbutazone. The test was based on the test of Randall 8: Sellitto. Arch. Int. llrurnracodyn lll. 409-4l9 (1957) and consisted of administering orally by gavage 30. 90 or l00 mg. per kilogram of body weight. the analgesic compound with water (ml. per kilogram of body weight) in eight male rats weighing between I20 to 200 grams. A control group received an equivalent volume of water. One hour after the administration ol the compound. 0. l0 ml. of a 20% yeast suspension (Red Star Brand. primary dry type 600 in 0.9% saline) was injected into the sub-plantar area of the left hind paw of each rat in the drug treated group and the control group. The purpose of the injection is to provoke the formation of inflammatory edema.

At hour one after the injection of yeast. the control paw and the yeast inflammed paw of each rat in the drug treated group in the control group successively were compressed at the plantar surface by a stud with a surface area of about 9 mm. attached to a force displacement transducer (model FTO3 Grass) which was driven at a constant rate. The induced pressure was recorded on a strip chart recorder. When a pain reaction was evoked front the rat by the application of pressure. the amount of pressure was recorded; the pressure was recorded in paper pressure units (0 100). The difference between the amount of pressure required to evoke pain reaction between the control paw and inflammed paw among the drug treated group of rats and control group of rats serves as an index of analgesic activity. The measure of analgesic activity in the rats is expressed in percent. in reference to that of the in flantrned paw and non'inflammed paw. [(Pressurc units to evoke pain in inflammcd paw/pressure units to evoke pain in control paw) x 1001. The results are summarized in the following table.

Compound Dose Degree of Analgesia Administered Percent with in mg [kg Reference to the Controls Z-tG methoxy-Z' ti 23 napthytt-propion- H10 9 aldehyde hydroxyimino Z-(o' t) 75 methoxy -2-naphthyl) NH) 90 propane scmicarha/one of 0 l4 2-(6'-mcthuxy-1'- I00 78 naphthyl) propionaldehyde l.l drmethoxy- (l 75 2-th'-niethoxy- [It] Z -tttlphll\)ll proprioaldehydc hisull'tle atldition 0 product of 2-((i'- .10 87 rnethoxy'T-naphthyl) l00 l0$ propionaldehydt: aspirin t) 44 lili] ()2 phenylhutamne 0 dl EXAMPLE l7 The anti-pyretic activity of 2-(6'-methoxy-2'- naphthyl) propionaldehyde was compared to the antipyretic activity of aspirin.

Anti-pyrctic activity Female rats weighing 90l00 grams were used. The normal" rectal temperature of the rats was recorded at hour 0. followed by the injection of 2 ml. of yeast suspension (the yeast suspension is prepared by suspending one cake of Flcischman's yeast in 22 ml. 0.9% NaCl) subcutaneously (l ml. dorsally. l ml. ventrally). The injection sited are massaged to spread the suspension beneath the skin. The yeast injection induces elevated body temperature. At hour 17, the rats were massaged again to stimulate a further increase in body temperature. (It was found that handling the rats at the time the second temperature was taken resulted in a rise in body temperature.) At hour 18. the second rectal temperature was recorded. after which the test material was administered orally by gravage in lml. agueous vehicle. (The aqueous vehicle consists oft).9% NaCl. 0.4% polysorbate 80. 0.5% carboxymethyl cellulose. 0.9% benzyl alcohol and water.) The third rectal temperature was obtained two hours after administration of the test material. The degree of antipyrctie activity was measured as a reduction in temperature (F) from the second to the third temperature readings (temperature at hour l8 temperature at hour 20) with respect to a control. The results are shown in the following table.

The above ingredients are thoroughly mixed and processed into single scored tablets. one tablet being administered every 3 to 4 hours.

EXAMPLE 1) lngrcdicnts Quantity per tablet. mgs

Z-to' mcthmy-2' naphthyli so ptopionaltleltydc cornstarch .li'i lactose 150 magnesium stcaraic I The above ingredients are mixed intimately and pressed into single scored tablets.

EXAMPLE 2() lngretlients Quantity per capsule. mgs.

Z-i mcthoxy-2'-naphth)'l) l5 propionaldehyde lactose 225 dcctrosc l() The above ingredients are mixed and introduced into a No. l hard-shell gelatin capsule.

EXAMPLE 2] Ingredients Quantity per capsule. mgs.

|.l-t|tinethmy-2-t$'- mclhox)-Z"1\ttphlh)ll ethane lactose 225 The above ingredients are mixed and introduced into No. l hard-shell gelatin capsule.

Similarly. the 2-(2'-naphthyl) aeetaldehyde derivatives prepared in or by means of the processes of Examples l-l 2 can be formulated as described above.

What is claimed is:

l. A compound selected from the group of compounds represented by the formula:

oil

R1 R5 i H wherein.

R is CHR'R or CH(OH) (SO Y); R and R" taken together are 3-hydroxypropylene-l.Z-dioxy. OCHRCHR O or -OCHR.. CRR"CHR O; each of R and R independently of each other. is hydrogen. alkyl having up to six carbon atoms. cycloalkyl having three to seven carbon atoms. cycloalkylmethyl having four to eight carbom atoms. 2-cycloalkylethyl having five to nine carbon atoms. phenyl. benzyl. a phenyl or benzyl substituted with up to two methyl. ethyl. isopropyl. methoxy. hydroxy. or chloro groups or up to three fluoro groups. R. is hydrogen. methyl. ethyl or propyl'. Y is sodium or potassium;

one of R and R is hydrogen. the other is hydrogen. methyl. ethyl or difluoromethyl'. or R and R taken together are methylene. halomethylene or ethylene; and

R" is alkyl having up to six carbon atoms. eycloalkyl having three to seven carbon atoms. hydroxymethyl. alkoxymethyl having two to seven carbon atoms. triiluoromethyl. vinyl ethynyl. fluoro. chloro. hydroxy or a hydrocarbon carboxylic acid ester having one to 12 carbon atoms. alkoxymethyloxy having two to seyen carbon atoms. difluoromethoxy. alltylthio having up to l2 carbon atoms. alkylthio substituted with one or two hydroxy. alkoxy. alkylthio or halo groups and having up to 12 carbon atoms. t'ormyl. acetyl 0r phenyl. or phenyl substituted with up to two methyl. ethyl. isopropyl. methoxy. hydroxy. or chloro groups. or up to three fluoro groups.

2. The compound according to claim 1 wherein R is -CHR'R. and R and R taken together are ethylenedioxy. 1.2-propylcnedioxy. l.3-propanedioxy. 3-hydroxypropylene-l.Z-dioxy. 2.3-butancdioxy. 1.2- diphenylethylcnedioxy. l.Z-dieyclopentylethyienc' dioxy. l.2-dibenzylethylenedioxy. 2.2-dimethyl-l.3- propanedioxy or 2-phenyl-l.3-propanedioxy.

3. The compound of claim 2 wherein one ol R" and R is hydrogen. the other is hydrogen. methyl or dii'luoromethyl; or R" and R taken together are methylene or difluoromethylene.

4. The compound of claim 2 wherein one of R and R is hydrogen. and the other is methyl.

5. The compound ofclaim I wherein R is CHR'R; R' and R taken together are ethylenedioxy or 3'-hydroxypropylene-l. 2'-dioxy; one of R and R is hydrogen. the other is hydrogen or methyl; or R and R taken together are methylene or difluoromethylene; and R" is methyl. trifluoromethyl. fluoro. chloro. methylthio. methoxymethylthio or difluoromethylthio.

6. A compound of claim 5 wherein the compound is the ethylene acetal ot' 2-(h'-methyl-2'- naphthyllacetaldehyde.

7. A compound of claim 5 wherein the compound is the ethylene acetal of 2-(6'-methylthio-2'- naphthyl)acetaldehyde.

8. A compound of claim 5 wherein the compound is the ethylene acetal of 2-(o-methyi-2'-naphthyllpropionaldehydc.

is the sodium bisulfite addition product of 246'- methyl-2'-naphthyl)acetaldehyde.

14. A compound ofclaim 11 wherein the compound is the sodium bisulfite addition product of z-m" methylthio-Z'-naphthyl(acetaldehyde.

15. A compound of claim ll wherein the compound is the sodium hisulfite addition product of Z-lh'- methyl-2'naphth vllpropionaldehydci 16. A compound of claim ll wherein the compound is the sodium hisulfitc addition product of 2-( methylthiol naphthyl)propionaldehydc.

at x x 

2. The compound according to claim 1 wherein R is -CHR1R2, and R1 anD R2 taken together are ethylenedioxy, 1,2-propylenedioxy, 1,3-propanedioxy, 3-hydroxypropylene-1,2-dioxy, 2,3-butanedioxy, 1,2-diphenylethylenedioxy, 1,2-dicyclopentylethylenedioxy, 1,2-dibenzylethylenedioxy, 2,2-dimethyl-1,3-propanedioxy or 2-phenyl-1,3-propanedioxy.
 3. The compound of claim 2 wherein one of R6 and R7 is hydrogen, the other is hydrogen, methyl or difluoromethyl; or R6 and R7 taken together are methylene or difluoromethylene.
 4. The compound of claim 2 wherein one of R6 and R7 is hydrogen, and the other is methyl.
 5. The compound of claim 1 wherein R is -CHR1R2; R1 and R2 taken together are ethylenedioxy or 3''-hydroxypropylene-1'', 2''-dioxy; one of R6 and R7 is hydrogen, the other is hydrogen or methyl; or R6 and R7 taken together are methylene or difluoromethylene; and R16 is methyl, trifluoromethyl, fluoro, chloro, methylthio, methoxymethylthio or difluoromethylthio.
 6. A compound of claim 5 wherein the compound is the ethylene acetal of 2-(6''-methyl-2''-naphthyl)acetaldehyde.
 7. A compound of claim 5 wherein the compound is the ethylene acetal of 2-(6''-methylthio-2''-naphthyl)acetaldehyde.
 8. A compound of claim 5 wherein the compound is the ethylene acetal of 2-(6''-methyl-2''-naphthyl)propionaldehyde.
 9. A compound of claim 5 wherein the compound is the ethylene acetal of 2-(6''-methylthio-2''-naphthyl)propionaldehyde.
 10. The compound of claim 1 wherein R is -CH(OH) (SO3Y).
 11. The compound of claim 1 wherein R is - CH(OH) (SO3Y), is one of R6 and R7 is hydrogen, the other is hydrogen or methyl, and Y is sodium.
 12. The compound of claim 11 wherein R16 is methyl, trifluoromethyl, fluoro, chloro, methylthio, methoxymethylthio, or difluoromethylthio.
 13. A compound of claim 11 wherein the compound is the sodium bisulfite addition product of 2-(6''-methyl-2''-naphthyl)acetaldehyde.
 14. A compound of claim 11 wherein the compound is the sodium bisulfite addition product of 2-(6''-methylthio-2''-naphthyl(acetaldehyde.
 15. A compound of claim 11 wherein the compound is the sodium bisulfite addition product of 2-(6''-methyl-2''-naphthyl)propionaldehyde.
 16. A compound of claim 11 wherein the compound is the sodium bisulfite addition product of 2-(6''-methylthio-2''-naphthyl)propionaldehyde. 